Changes

==Primary Author(s)*==

==Primary Author(s)*==

Madina Sukhanova, PhD, FACMG Northwestern University

Madina Sukhanova, PhD FACMG Northwestern University

__TOC__

__TOC__

==Cancer Category/Type==

==Cancer Category/Type==

==Cancer Sub-Classification / Subtype==

==Cancer Sub-Classification / Subtype==

==Epidemiology / Prevalence==

==Epidemiology / Prevalence==

The 2021 WHO classified this entity as pediatric-type based on well defined studies characterized by negative molecular features of H3 and IDH  <ref name=":1" /><ref>{{Cite journal|last=Mackay|first=Alan|last2=Burford|first2=Anna|last3=Molinari|first3=Valeria|last4=Jones|first4=David T. W.|last5=Izquierdo|first5=Elisa|last6=Brouwer-Visser|first6=Jurriaan|last7=Giangaspero|first7=Felice|last8=Haberler|first8=Christine|last9=Pietsch|first9=Torsten|date=2018-05-14|title=Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial|url=https://pubmed.ncbi.nlm.nih.gov/29763623|journal=Cancer Cell|volume=33|issue=5|pages=829–842.e5|doi=10.1016/j.ccell.2018.04.004|issn=1878-3686|pmc=5956280|pmid=29763623}}</ref><ref name=":2">{{Cite journal|last=Korshunov|first=Andrey|last2=Schrimpf|first2=Daniel|last3=Ryzhova|first3=Marina|last4=Sturm|first4=Dominik|last5=Chavez|first5=Lukas|last6=Hovestadt|first6=Volker|last7=Sharma|first7=Tanvi|last8=Habel|first8=Antje|last9=Burford|first9=Anna|date=2017-09|title=H3-/IDH-wild type pediatric glioblastoma is comprised of molecularly and prognostically distinct subtypes with associated oncogenic drivers|url=https://pubmed.ncbi.nlm.nih.gov/28401334|journal=Acta Neuropathologica|volume=134|issue=3|pages=507–516|doi=10.1007/s00401-017-1710-1|issn=1432-0533|pmid=28401334}}</ref> which have focused only on pediatric patients; thus, the frequency of this tumor type in adults in unknown. Median reported age of patients at the time of diagnosis was 9.8 years. One study reported male prevalence.<ref name=":2" />

The 2021 WHO classified this entity as pediatric-type, based on well defined studies focusing on a pediatric population with gliomas characterised by IDH-/H3-wildtype status<ref name=":1" /><ref>{{Cite journal|last=Mackay|first=Alan|last2=Burford|first2=Anna|last3=Molinari|first3=Valeria|last4=Jones|first4=David T. W.|last5=Izquierdo|first5=Elisa|last6=Brouwer-Visser|first6=Jurriaan|last7=Giangaspero|first7=Felice|last8=Haberler|first8=Christine|last9=Pietsch|first9=Torsten|date=2018-05-14|title=Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial|url=https://pubmed.ncbi.nlm.nih.gov/29763623|journal=Cancer Cell|volume=33|issue=5|pages=829–842.e5|doi=10.1016/j.ccell.2018.04.004|issn=1878-3686|pmc=5956280|pmid=29763623}}</ref><ref name=":2">{{Cite journal|last=Korshunov|first=Andrey|last2=Schrimpf|first2=Daniel|last3=Ryzhova|first3=Marina|last4=Sturm|first4=Dominik|last5=Chavez|first5=Lukas|last6=Hovestadt|first6=Volker|last7=Sharma|first7=Tanvi|last8=Habel|first8=Antje|last9=Burford|first9=Anna|date=2017-09|title=H3-/IDH-wild type pediatric glioblastoma is comprised of molecularly and prognostically distinct subtypes with associated oncogenic drivers|url=https://pubmed.ncbi.nlm.nih.gov/28401334|journal=Acta Neuropathologica|volume=134|issue=3|pages=507–516|doi=10.1007/s00401-017-1710-1|issn=1432-0533|pmid=28401334}}</ref>. Therefore, the frequency of this tumor type in adults in unknown. The median reported age of patients at the time of diagnosis was 9.8 years. One study reported male prevalence.<ref name=":2" />

==Clinical Features==

==Clinical Features==

Other sites: brainstem, and cerebellum.<ref name=":2" />

Other sites: brainstem, and cerebellum.<ref name=":2" />

Although most of molecular subtypes of dpHGG involve supratentorial brain (96% of dpHGG RTK2, 86% of dpHGG MYCN, and 82% of dpHGG RTK1 tumors), 4% of dpHGG RTK2, 14% of dpHGG MYCN, and 18% of dpHGG RTK1 cases can involve infratentorial/brainstem sites.<ref name=":2" />

Although most of molecular subtypes of dpHGG involve the supratentorial compartment (96% of dpHGG RTK2; 86% of dpHGG MYCN; 82% of dpHGG RTK1 tumors), a lesser proporton can involve infratentorial/brainstem sites (4% of dpHGG RTK2;14% of dpHGG MYCN; 18% of dpHGG RTK1 cases).<ref name=":2" />

==Morphologic Features==

==Morphologic Features==

Morphology of dHGGs, H3-/IDH-wildtype, is consistent with glioblastoma-like features with high cellularity, mitotic activity, microvascular proliferation, and necrosis; however, undifferentiated morphology and areas of glial differentiation can also be noted. pHGG MYCN molecular subtype often consists of large cells with distinct nucleoli, spindle-shaped and epithelioid cells and also reveals areas of diffuse infiltration and circumscribed nodules.<ref name=":3" />  

The morphology of dHGGs, H3-/IDH-wildtype, shows glioblastoma-like features with high cellularity, mitotic activity, microvascular proliferation, and necrosis; however, undifferentiated, primitive morphology and areas of glial differentiation can also be noted within the same case. The pHGG MYCN molecular subtype often consists of large cells with distinct nucleoli admixed with spindle-shaped and epithelioid cells; the architecture of these tumours can show areas of diffuse infiltration, in combinaiton with circumscribed nodules.<ref name=":3" />  

==Immunophenotype==

==Immunophenotype==

!Finding!!Marker

!Finding!!Marker

|-

|-

|Positive (universal)||Neoplastic glial component – GFAP, and/or OLIG2.<ref name=":0" /><ref name=":1" />

|Positive (universal)||Neoplastic glial component – GFAP, and/or OLIG2<ref name=":0" /><ref name=":1" />

|-

|-

|Positive (subset)||dpHGG MYCN molecular subtype can be positive for neuronal markers.

|Positive (subset)||dpHGG MYCN molecular subtype can be positive for neuronal markers

|-

|-

|Negative (universal)|| IDH1 R132H (normal retained pattern of staining).

|Negative (universal)|| IDH1 R132H

H3 p.K28me3 (K27me4) (preserved expression).<ref name=":3" />  

H3 p.K28me3 (K27me3) (preserved expression)<ref name=":3" />

|-

|-

|Negative (subset)||dpHGG MYCN molecular subtype can be negative for glial marker GFAP, and/or OLIG2.

|Negative (subset)||dpHGG MYCN molecular subtype can be negative for glial marker GFAP, and/or OLIG2

|}

|}

==Chromosomal Rearrangements (Gene Fusions)==

==Chromosomal Rearrangements (Gene Fusions)==

 

{| class="wikitable sortable"

{| class="wikitable sortable"

|-

|-

!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence

!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Structural  variation!!Prevalence

!Diagnostic Significance (Yes, No or Unknown)

!Diagnostic Significance (Yes, No or Unknown)

!Prognostic Significance (Yes, No or Unknown)

!Prognostic Significance (Yes, No or Unknown)

!Notes

!Notes

|-

|-

|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)

|t(3;3)(p21.31;p25.2)

EXAMPLE 30% (add reference)

|Yes

|deletion

|No

|11%<ref name=":4" />

|Yes

|EXAMPLE

 

The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).

|Results in constitutive activation of kinase domain<ref name=":4" />

|-

|t(7;7)(q31.2;q31.32)||PTPRZ1::MET||deletion||22%<ref name=":4" />

|t(7;7)(q31.2;q31.32)

|11%<ref name=":4" />

|Unknown

|Unknown

|Unknown

|Concurrent MET amp is frequently noted<ref name=":4" />

|t(9;9)(p31.32;p21.33)

|}

|}

==Individual Region Genomic Gain/Loss/LOH==

==Individual Region Genomic Gain/Loss/LOH==

{| class="wikitable sortable"

{| class="wikitable sortable"

!Notes

!Notes

|-

|-

|EXAMPLE

|2

 

|EXAMPLE Loss

|EXAMPLE

 

chr7:1- 159,335,973 [hg38]

|EXAMPLE

 

|-

chr7

|2

|Yes

|Yes

|chr2:8,682,056-8,684,461 [GRCh38]

|Yes [33% of dpHGG RTK1 subtype]

|No<ref name=":2" />

|chr7:55,019,017-55,211,628 [GRCh38]

|Yes [50% of dpHGG RTK2 subtype]

|-

|No

|No

|EXAMPLE

|Worse outcome<ref name=":2" />

 

Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference). Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).

|Deletions result in bi-allelic loss of CDKN2A/B seen in 6% MYCN subtype, 27% RTK1 subtype; 72% RTK2 subtype.<ref name=":2" /><ref name=":4" />

|-

|-

|EXAMPLE

|12 / 7

 

|Amplification

|CDK4 - chr12:57,747,727-57,752,310 [GRCh38]

|EXAMPLE Gain

CDK6 - chr7:92,604,921-92,836,573 [GRCh38]

|EXAMPLE

|12q14.1 / 7q21.2

 

chr8:1-145,138,636 [hg38]

|EXAMPLE

 

|No

|No

|No

|Unknown

|No

|Unknown

|EXAMPLE

|Ampifications of CDK4/6 seen in 22% MYCN subtype, 9% RTK1 subtype; 17% RTK2 subtype.<ref name=":2" />

 

Common recurrent secondary finding for t(8;21) (add reference).

|}

|}

==Characteristic Chromosomal Patterns==

==Characteristic Chromosomal Patterns==

{| class="wikitable sortable"

{| class="wikitable sortable"

!Notes

!Notes

|-

|-

|EXAMPLE

|Chromosome 7 gain

 

|Yes

|Yes

|No

|No

|No

|No

|EXAMPLE:

|No

 

|Recurrent finding in 42% MYCN subtype; 12% RTK1 subtype; 50% RTK2 subtype.<ref name=":2" />

See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

|}

|}

==Gene Mutations (SNV/INDEL)==

==Gene Mutations (SNV/INDEL)==

{| class="wikitable sortable"

{| class="wikitable sortable"

!Notes

!Notes

|-

|-

|EXAMPLE: TP53; Variable LOF mutations

|PDGFRA

 

|Not stated in literature; referred to in the WHO Classification<ref name=":6" />

 

|unclear

EGFR; Exon 20 mutations

|IDH1/2, H3<br />

 

EXAMPLE: BRAF; Activating mutations

|Unknown

|EXAMPLE: TSG

|Unknown

|EXAMPLE: 20% (COSMIC)

 

|EXAMPLE: IDH1 R123H

|EXAMPLE: EGFR amplification

|

|

|

|

|

|

|}

|}

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

==Epigenomic Alterations==

==Epigenomic Alterations==

==Genes and Main Pathways Involved==

==Genes and Main Pathways Involved==

Put your text here and fill in the table

The pHGG, H3/IDH-wildtype frequently reveals variants in genes encoding members of the TAS/MAPK and PI3K pathways.<ref name=":4" />

{| class="wikitable sortable"

{| class="wikitable sortable"

|-

|-

!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome

!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome

|-

|-

|EXAMPLE: BRAF and MAP2K1; Activating mutations

|MET; activating alterations

|EXAMPLE: MAPK signaling

|MAPK/ERK pathway activation

|EXAMPLE: Increased cell growth and proliferation

|Increased cell growth and proliferation

|-

|-

|EXAMPLE: CDKN2A; Inactivating mutations

|RAF1; activating alterations

|EXAMPLE: Cell cycle regulation

|MAPK/ERK pathway activation

|EXAMPLE: Unregulated cell division

|Increased cell growth and proliferation

|-

|-

|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations

|NTRK2; activating alterations

|EXAMPLE:  Histone modification, chromatin remodeling

|MAPK/ERK pathway activation

|EXAMPLE:  Abnormal gene expression program

|Increased cell growth and proliferation

|}

|}

==Genetic Diagnostic Testing Methods==

==Genetic Diagnostic Testing Methods==

==Familial Forms==

==Familial Forms==

Germline mutations of genes involved in the mismatch repair (MMR) system can be associated with a proportion of pHGG cases,<ref>{{Cite journal|last=Dodgshun|first=Andrew J.|last2=Fukuoka|first2=Kohei|last3=Edwards|first3=Melissa|last4=Bianchi|first4=Vanessa J.|last5=Das|first5=Anirban|last6=Sexton-Oates|first6=Alexandra|last7=Larouche|first7=Valérie|last8=Vanan|first8=Magimairajan I.|last9=Lindhorst|first9=Scott|date=2020-11|title=Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns|url=https://pubmed.ncbi.nlm.nih.gov/32895736|journal=Acta Neuropathologica|volume=140|issue=5|pages=765–776|doi=10.1007/s00401-020-02209-8|issn=1432-0533|pmid=32895736}}</ref><ref>{{Cite journal|last=Alphones|first=Sheena|last2=Chatterjee|first2=Uttara|last3=Singh|first3=Angad|last4=Das|first4=Anirban|last5=Zameer|first5=Lateef|last6=Achari|first6=Rimpa|last7=Bhattacharya|first7=Arpita|last8=Roy|first8=Paromita|date=2021-08|title=Immunohistochemical screening for mismatch repair protein deficiency in paediatric high-grade gliomas - institutional experience and review of literature|url=https://pubmed.ncbi.nlm.nih.gov/34097097|journal=Child's Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery|volume=37|issue=8|pages=2521–2530|doi=10.1007/s00381-021-05229-1|issn=1433-0350|pmid=34097097}}</ref><ref>{{Cite journal|last=Amayiri|first=Nisreen|last2=Tabori|first2=Uri|last3=Campbell|first3=Brittany|last4=Bakry|first4=Doua|last5=Aronson|first5=Melyssa|last6=Durno|first6=Carol|last7=Rakopoulos|first7=Patricia|last8=Malkin|first8=David|last9=Qaddoumi|first9=Ibrahim|date=2016-01-15|title=High frequency of mismatch repair deficiency among pediatric high grade gliomas in Jordan|url=https://pubmed.ncbi.nlm.nih.gov/26293621|journal=International Journal of Cancer|volume=138|issue=2|pages=380–385|doi=10.1002/ijc.29724|issn=1097-0215|pmid=26293621}}</ref> typically of the pHGG RTK1 subtype.

 

==Additional Information==

 

 

==Links==

 

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==References==

==References==

<references />

<references />

 

 

==Notes==

==Notes==

<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.

<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.